Abstract
A swelling-activated, background K+ current in the corneal epithelium is characteristically activated by fenamates and inhibited by diltiazem. Fatty acids also stimulate this current, indicating that its origin is a lipid-sensitive mechano-gated 2P domain K+ channel. In the present study, modulation of TREK-1, TREK-2, and TRAAK channels by fenamates and diltiazem was examined. TREK-1, TREK-2, and TRAAK currents transiently expressed in COS-7 cells were recorded by the perforated-patch configuration. As previously reported, arachidonic acid (20 μM) stimulated all of these channels, and a volatile anesthetic, halothane (1 mM) augmented TREK-1 and TREK-2 but not TRAAK. Flufenamic acid (FA, 100 μM), niflumic acid (NA, 100 μM), and mefenamic acid (MA, 100 μM) markedly stimulated TREK-1, TREK-2, and TRAAK. The potency sequence for the activation of TREK-1 and TREK-2 was FA > NA = MA, and the potency sequence for the activation of TRAAK was FA = NA > MA. Diltiazem (1 mM) inhibited TREK-1 and TREK-2, but not TRAAK. In conclusion, fenamates are openers of the lipid-sensitive mechano-gated 2P domain K+ channels, and diltiazem may be a specific blocker for TREK. These novel findings could help to further understand channel functions of the mechano-gated 2P domain K+ channels.
References
Greenwood IA, Large WA (1995) Comparison of the effects of fenamates on Ca-activated chloride and potassium currents in rabbit portal vein smooth muscle cells. Br J Pharmacol 116:2939–2948
Lesage F, Terrenoire C, Romey G, Lazdunski M (2000) Human TREK2, a 2P domain mechano-sensitive K+ channel with multiple regulations by polyunsaturated fatty acids, lysophospholipids, and Gs, Gi, and Gq protein-coupled receptors. J Biol Chem 275:28398–28405
Lesage F, Maingret F, Lazdunski M (2000) Cloning and expression of human TRAAK, a polyunsaturated fatty acids-activated and mechano-sensitive K+ channel. FEBS Lett 471:137–140
Ottolia M, Toro L (1994) Potentiation of large conductance KCa channels by niflumic, flufenamic, and mefenamic acids. Biophys J 67:2272–2279
Patel AJ, Honore E, Lesage F, Fink M, Romey G, Lazdunski M (1999) Inhalational anesthetics activate two-pore-domain background K+ channels. Nat Neurosci 2:422–426
Patel AJ, Honore E (2001) Properties and modulation of mammalian 2P domain K+ channels. Trends Neurosci 24:339–346
Rae JL, Farrugia G (1992) Whole-cell potassium current in rabbit corneal epithelium activated by fenamates. J Membr Biol 129:81–97
Takahira M, Sakurada N, Segawa Y, Shirao Y (2001) Two types of K+ currents modulated by arachidonic acid in bovine corneal epithelial cells. Invest Ophthalmol Vis Sci 42:1847–1854
Acknowledgements
The authors thank Bret A Hughes at University of Michigan and Hiroshi Sakurai for critical evaluation of the manuscript. This research was supported by Grant-in-Aid 11771043 and 13771018 for MT from the Ministry of Education, Japan.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Takahira, M., Sakurai, M., Sakurada, N. et al. Fenamates and diltiazem modulate lipid-sensitive mechano-gated 2P domain K+ channels. Pflugers Arch - Eur J Physiol 451, 474–478 (2005). https://doi.org/10.1007/s00424-005-1492-5
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00424-005-1492-5